This application is a competitive renewal of the Dana-Farber/Harvard Cancer Center (DF/HCC) Lung Cancer Specialized Program in Research Excellence (SPORE). The Dana-Farber/Harvard Cancer Center Lung Cancer SPORE includes investigators from the Harvard-affiliated hospitals in Boston, Harvard Medical School, and the Harvard School of Public Health. This DF/HCC Lung Cancer SPORE will build on the strengths of established ongoing scientific investigation within the DF/HCC. Five major projects are proposed. Project 1 will use single nucleotide polymorphisms in germline DMA to examine their associations with patient outcome following treatment for non-small cell lung cancer. Project 2 will examine the transcription factors Foxa2 and the C/EBP family members in the pathogenesis and potential treatment of lung cancer. Project 3 plans to target erlotinib-resistant lung cancer with other tyrosine kinase inhibitors and irradiation to provide further information on effective combinations of targeted agents. Project 4 will characterize the effect of Hsp90 inhibitors in NSCLCs with different genomic changes to help identify patients who may benefit from this therapy. Project 5 will study the mechanisms of acquired resistance to epidermal growth factor receptor-targeted agents in cell lines and human trials for patients with lung cancer. The 4 cores established in 2003 integrate these Projects. These include 1) Tissue and Pathology Core, 2) Administration, Evaluation and Planning Core, 3) Biostatistics Core, 4) Genomics and Bioinformatics Core. This SPORE application describes a Development Research Program that includes our past performance and plan for selection of new projects. The Career Development Program describes our recipients and outlines the mechanism for the identification and support of talented young investigators in lung cancer. The Developmental Research and Career Development Programs will provide the focus for involvement of the community in planning and financial support of the DF/HCC Lung Cancer SPORE. The goal of the DF/HCC Lung Cancer SPORE is to continue the translation of biological and technological advances into clinically meaningful advances for patients with lung cancer and at risk for lung cancer.